A range of important classes of pharmaceutical compounds, food additives and other biologically active compounds are based on chiral alkyl amines. Such classes of compounds include the sympathomimetic amines, such as ephedrine (α-[1-(methylamino)ethyl]benzene-methanol). Many of these compounds are commercially important and are synthesised for use in pharmaceutical compositions and in other applications.
Physicochemical methods for production of enantiomerically pure compounds usually involve multi-step synthesis incorporating one or more steps which are asymmetric, and laborious purification procedures. Such methods are not only tedious, but frequently provide relatively poor yields. Alternatively enantiomerically-pure starting materials can be used, together with enantioselective reaction steps; however, such pure starting materials are available only for a very limited number of desired compounds.
In recent years, intense efforts have been directed towards development of methods which are highly selective, provide a good rate of transformation, and enable easy, non-chromatographic separation and purification of the product. It has also been considered particularly desirable for the reactions to be carried out in non-aqueous solvents, since these are particularly convenient for large scale reactions and purifications.
Ephedrine (α-[1-(methylamino)ethyl]benzene-methanol), originally isolated from plants of the genus Ephedra, occurs as the naturally-occurring isomers 1-ephedrine and d-pseudoephedrine, and other pharmacologically active isomers include d-ephedrine and 1-pseudoephedrine. These compounds are adrenergic sympathomimetic agents and have antihistamine activity; 1-ephedrine is widely used as a bronchodilator, while d-pseudoephedrine is widely used as a decongestant. Compounds of these groups are present in a very wide range of prescription and over-the-counter pharmaceutical formulations.
The production of 1-phenylacetylcarbinol, a precursor of 1-ephedrine, by catalysis using whole baker's yeast cells in aqueous medium was one of the first microbial biotransformation processes to be used commercially (Neuberg and Hirsch, 1921; see also Hildebrandt and Klavehn, 1934). This reaction involves the yeast-induced condensation of benzaldehyde with acetyl-coenzyme A. The reaction has been widely investigated, and has been shown to be mediated by the enzyme pyruvate decarboxylase (Groger, Schmander and Mothes, 1966). It has also been shown that the reaction has a relatively broad specificity for the substrate, enabling a variety of substituted aromatic aldehydes to be converted to the corresponding substituted optically-active phenylacetylcarbinols (Long, James and Ward, 1989).
Although this yeast-catalysed system has been widely exploited, this has normally utilised aqueous systems, which are inconvenient for large-scale extraction and purification, which require organic solvents. Additionally, fermentation systems present the disadvantage that purification of the desired product can be difficult, and yields tend to be low; while the yield and convenience of the reaction can be improved by utilising immobilised cells, or cells which have been selected or genetically, modified, this adds significantly to the cost of the process. The use of purified enzymes is normally prohibitively expensive, and again without the use of immobilised enzymes the yields tend to be low and purification difficult.
In our earlier International Application PCT/AU00/01543, we showed that yeast-mediated acyloin condensation of benzaldehyde can be achieved in supercritical or liquefied carbon dioxide or in liquefied petroleum gas. This reaction results in superior conversion of the aromatic aldehydes to the desired carbinol when compared with the corresponding reaction conducted in conventional organic solvents. In a preferred embodiment, yields of around 79% with the total absence of side-products were obtained using the method of the invention.
Based on experiments with other ketones and aldehydes, it was believed that reductive amination of the carbinol could not be conducted in any mediums other than conventional organic solvents. Accordingly, the difficulty still remained that the intermediate had to be converted into 1-ephedrine using conventional techniques in conventional organic solvents.
It has now surprisingly been found by the present applicant that reductive amination of the ketone precursor for ephedrine can be conducted in the presence of supercritical fluids or liquefied gases such as supercritical carbon dioxide or liquefied petroleum gas. These reagents are especially advantageous to use as the reaction medium in large scale reactions since the purification and processing of the products is simpler than comparable reactions conducted in standard organic or aqueous solvents.
Similarly, the applicant has found that particular ketone precursors for compounds structurally related to ephedrine can be subjected to reductive amination to form the target amines in supercritical fluids or liquefied gases.
Since carbon dioxide is non-toxic and can be readily recycled, this method avoids the problems associated with reactions involving organic solvents. Moreover, when combined with earlier reactions or processes conducted in the same solvent, the target compound can be made in a “one-pot” process, thereby further maximising possible yields and simplifying large scale operations for the synthesis of the compound.